Synthesis of N-Oxyureas by Substitution and Cope-Type Hydroamination Reactions Using O-Isocyanate Precursors

Article abstract of DOI:10.1021/acs.orglett.7b03288

Oxy-carbamate O-isocyanate precursors facilitate access to synthetically valuable N-oxyureas via substitution with amines. This work exploits the reactivity of suitable O-isocyanate precursors, identified by a thorough study highlighting the different reactivity of isocyanate masking groups. This led to bench-stable O-isocyanate precursors, offering improved versatility in the synthesis of N-oxyureas, and demonstrates the controlled reactivity of masked O-isocyanates. Suitable precursors also enabled the first example of Cope-type hydroamination of unsaturated hydroxyureas.

Full text of DOI:10.1021/acs.orglett.7b03288

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Synthesis of N‑Oxyureas by Substitution and Cope-Type
Hydroamination Reactions Using O‑Isocyanate Precursors
†
†
́
Meredith A. Allen, Ryan A. Ivanovich, Dilan E. Polat, and Andre M. Beauchemin*
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa,
1
0 Marie-Curie, Ottawa, ON K1N 6N5, Canada
*
S Supporting Information
ABSTRACT: Oxy-carbamate O-isocyanate precursors facilitate access
to synthetically valuable N-oxyureas via substitution with amines. This
work exploits the reactivity of suitable O-isocyanate precursors, identified
by a thorough study highlighting the different reactivity of isocyanate
masking groups. This led to bench-stable O-isocyanate precursors,
offering improved versatility in the synthesis of N-oxyureas, and
demonstrates the controlled reactivity of masked O-isocyanates. Suitable
precursors also enabled the first example of Cope-type hydroamination of unsaturated hydroxyureas.
ydroxamates and hydroxamic acids have many uses
isocyanates, however; are considerably scarcer, with less than
100 publications relating to nitrogen-substituted isocyanates
6,7
1
2
H
as synthetic intermediates, chiral ligands, and directing
3
5
groups and are also common pharmacophores in enzyme inhib-
(N-isocyanates) and less than 20 relating to O-isocyanates.
4
itors. Their nitrogen-substituted analogs, N-oxyureas, have
garnered interest for similar applications and are also key sub-
units in agrochemicals and pharmaceuticals (e.g., Scheme 1A).
O-Isocyanates are particularly difficult to manipulate due to their
propensity to trimerize or to undergo Lossen rearrangements
8
,9
through cleavage of the N−O bond. Until recently, there
was only one reported example of controlled reactivity of an
O-isocyanate, which was formed in situ from precursors con-
Scheme 1. Synthesis and Applications of N-Oxyureas
10,11
taining an imidazole blocking (masking) group.
This
pioneering work by BMS chemists showed that trimerization
can be avoided through in situ isocyanate formation, likely by
controlling the concentration of O-isocyanate available. How-
ever, only the reactivity of BnO−NCO precursors was studied,
and limitations to the reaction scope were present. Recently, we
became interested in using different masked O-isocyanate
precursors (i.e., bench-stable, blocking group: phenol) in cas-
cade reactions yielding hydroxylamine-containing hetero-
12
cycles (Scheme 2). Given the strict control required to achieve
cascade reactions, and the importance of the N-oxyureas, a
Scheme 2. Previous and Current Work with O-Isocyanates
However, the synthetic methods to produce them are relatively
underdeveloped (Scheme 1B). Typically, access to N-oxyureas
relies on reactive acylating agents (Scheme 1B, left), and a
literature survey indicated that approaches based on the use of
oxy-carbamates need further development (Scheme 1B, right).
Specifically, our work on heteroatom-substituted isocyanates
suggested that the use of suitable oxy-carbamates as precursors to
oxygen-substituted isocyanates (O-isocyanates) could yield a
reliable route to form N-oxyureas.
The importance of isocyanates is exemplified by the greater
than 4000 commercially available reagents and the millions of
tons produced and used every year. Heteroatom-substituted
Received: October 22, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7
a
thorough study of the substitution step was needed. Herein,
we report the development of broadly applicable substitution
reactions to form N-oxyureas, document reactivity differences
associated with different precursors, and use this reactivity in the
first examples of Cope-type hydroamination of N-hydroxyureas
use. In contrast, phenol-derived masked isocyanates proved
stable upon storage over prolonged periods of time, and pos-
15
sessed high reactivity under the conditions shown in Table 1.
Having determined the optimal leaving groups for a represen-
tative array of O-isocyanate precursors, we then studied the
effect of several amine nucleophiles on the substitution reaction
(Scheme 3).
(Scheme 2).
To explore the reactivity of the O-isocyanate precursors, we
first examined the ability of several oxy-carbamates and one
oxyurea to undergo O-isocyanate formation (Table 1), using
a
Scheme 3. O-Isocyanate Substitution: Amine Scope
Table 1. O-Isocyanate Substitution: Leaving Group (LG)
a
Investigation
b
entry precursor
LG
PhO
R
temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1a
1b
1c
1d
1e
1f
H
Et
Bz
H
Et
Bz
H
Et
H
H
H
H
70
16
0.5
2
71
94
57
58
99
87
PhO
PhO
120
120
rt
c
c
c
p-NO PhO
16
16
16
16
4
2
a
Conditions: for R = H, oxy-carbamate (1.1 equiv), amine (1.0 equiv),
p-NO PhO
rt
2
Et
For R = Et, oxy-carbamate (1.1 equiv), amine (1.0 equiv) in MeCN
N (0.2 equiv) in THF (0.3 M), stir in oil bath at 70 °C overnight.
3
p-NO PhO
rt
2
d
e
1g
1h
1j
EtO
EtO
120
120
70
0
(0.2 M), heat in μW at 120 °C for 30 min. For R = Bz, oxy-carbamate
(1.0 equiv), amine (1.05 equiv), imidazole (0.1 equiv) in THF
60
74
i-Pr N
16
16
16
16
2
(0.2 M), heat in μW at 100 °C for 3 h. Isolated yields are shown.
d
d
d
e
b
c
0
1
2
1k
1l
BnO
120
120
120
8
Five equiv of allylamine used. One equiv of Et N used.
3
e
CF CH O
4
3
2
e
1m
t-BuO
0
Gratifyingly, a variety of oxyureas could be formed using the
a
Conditions: for R = H, precursor (1.1 equiv), morpholine (1.0 equiv),
reaction of blocked O-isocyanates with nitrogen nucleophiles
(Scheme 3). Secondary aliphatic amines proved competent
nucleophiles for all carbamates used (3a−3f). Primary amines
initially led to lower yields under similar conditions, however,
using an excess (5 equiv) of the amine improved the yields
substantially (58−79%). The weakly nucleophilic N-methylani-
line proved a poor reaction partner and led to no substitution
under the reaction conditions for the hydroxy-carbamate 1a.
However, the corresponding alkyl and acyl examples underwent
substitution well (40%, 91%), though the ethoxyurea 3k was
difficult to isolate. The unprotected secondary ethanolamine
underwent a chemoselective substitution reaction with good to
excellent yields (3m−3o). With the scope of amine nucleophiles
explored, we turned our attention to the last variable of
the starting materials; the substitution on the oxygen of the
carbamate. The results of this study are shown in Scheme 4.
A variety of carbamates could be used for the substitution,
mostly with excellent yields, using di-n-propylamine as the
nucleophile (Scheme 4). As demonstrated during the leaving
group optimization, there was some variability in the yields based
on the oxygen substitution. The yield for hydroxy-carbamate 1a
was consistent with previous results (85%). The yields for
all alkoxy carbamates (4b−4e) were excellent (91 to 96%), as
expected. Lower yields were obtained when using acyloxy
carbamates with alkyl substituents (4f, 4g); however, when using
electron-rich, aromatic acyloxy carbamates (4h, 4i), the sub-
stitution yield remained excellent. In contrast, carbamates with
better leaving groups (1j−k) underwent uncontrolled Lossen
Et N (0.2 equiv) in THF (0.3 M), stir in oil bath overnight. For R = Et,
carbamate (1.1 equiv) and morpholine (1.0 equiv) in MeCN (0.2 M),
heat in μW to 120 °C. For R = Bz: carbamate (1.0 equiv), morpholine
3
(
1
1.05 equiv), imidazole (0.1 equiv) in THF (0.2 M), heat in μW at
b c
00 °C for 3 h. Isolated yield. Carbamate (1.0 equiv), morpholine
(
1.0 equiv), Et N (1.0 equiv) in CH Cl (0.08 M), stir at rt overnight.
3 2 2
d
Reactions at 70 and 100 °C result in no formation of product.
H NMR yield based on 1,3,5-trimethoxybenzene.
e
1
13
conditions similar to those used for N-isocyanates. As with
5
,11c
both carbon and nitrogen-substituted isocyanates,
the
masking (leaving) group of the isocyanate precursor determines
the conditions required for the release of the reactive inter-
mediates. During efforts to determine the ideal conditions for
substitution, it became apparent that hydroxy-carbamate
precursors (R = H, entries 1,4,7) underwent the substitution
considerably less efficiently than the alkoxy (R = Et, entries 2,5,8)
and acyloxy (R = Bz, entries 3,6) carbamates. The latter results
are noteworthy, given the absence of Lossen rearrangement
under the reaction conditions, and the high interest in such OBz
14
hydroxylamine derivatives as amination reagents. Already, the
significant differences in reactivity based on oxygen-substitution
highlighted the need for further work with hydroxy-, alkoxy-,
and acyloxy-substituted carbamates (see below). Susceptibility
to oxidation and isolation difficulties likely account for lower
yields for hydroxy-carbamates (R = H) and, consequently, led to
studies with other masking groups (entries 9−12).
Despite this survey, phenol remained the optimal leaving
group for the substitution on hydroxy-carbamates (entry 1).
Phenol also proved to be the optimal leaving group for the alkyl-
and acyl-substituted examples (entries 2, 3). Optimal conditions
for the p-nitrophenol leaving group were determined to be too
mild and required the addition of stoichiometric base, and the
corresponding precursors (1d−1f) were too unstable for regular
9,16
rearrangements and did not form the desired products (4j, 4k).
This clearly indicates that strong electron-withdrawing groups are
required for N−O bond cleavage to occur, even at 120 °C in the
presence of an amine base. Overall, the results in Schemes 3 and 4
show that variation of each reaction partner was generally well
tolerated. With an adequate understanding of the substitution
B
DOI: 10.1021/acs.orglett.7b03288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
18,21
Scheme 4. O-Isocyanate Substitution: Oxy-Carbamate Scope
the Cope-type hydroamination literature.
Reducing the
steric bulk of the second substituent on the allylamine results in a
similar yield, but necessitates an increased reaction time (5c).
The hydroamination reaction also formed the cyclic N-oxyurea
(
5d, 5e) with substituted allylamines with good yields.
Several limitations of this reactivity became apparent during
the scope of allylamines. Sterically bulky amines, such as N-tert-
butyl allylamine, did not undergo the necessary substitution to
furnish the cyclic hydroxamic acid product (5f). In contrast,
allylamine underwent substitution, but its adduct did not
undergo hydroamination under the optimized reaction con-
ditions (5g): this result suggests that only substrates derived
from secondary allylamines can access the urea rotamer required
for cyclization (i.e., with NHOH and allyl groups s-cis). To support
the likelihood of a concerted, Cope-type hydroamination pathway,
the ethoxyurea product (3e) was subjected to the hydroamination
conditions (eq 1). No product was observed, supporting the
a
Conditions: oxy-carbamate (1.05 equiv), n-Pr NH (1.0 equiv) in
2
MeCN (0.2 M), heat to 120 °C in μW for 30 min. Isolated yields are
1
shown ( H NMR yield based on 1,3,5-trimethoxybenzene shown in
b
parentheses). Hydroxy-carbamate (1.1 equiv), Et N (0.2 equiv)
3
c
added, stirred at 70 °C in oil bath overnight. Acyloxy-carbamate
(
1.0 equiv), amine (1.05 equiv), imidazole (0.1 equiv) in THF (0.2 M),
Cope-type pathway since 3e lacks the hydrogen atom required
d
17,18
heat to 100 °C in μW for 1−3 h. Uncontrolled formation of products
derived from a Lossen rearrangement was observed.
for the planar, five-membered transition state.
To our
knowledge, this reaction sequence therefore includes the first
example of Cope-type hydroaminations of hydroxyureas or
hydroxamic acid derivatives. Not surprisingly, the electron-
withdrawing nature of the carbonyl group and rotamer issues
result in the need to use significantly higher reaction temper-
atures (see SI for details).
of O-isocyanates, we turned our attention to the reactivity of the
N-oxyurea products.
Given our interest in metal-free, Cope-type hydroaminations
17,18
using hydroxylamines,
we recognized the possibility to
develop a substitution and hydroamination cascade with
hydroxy-carbamate O-isocyanate precursor 1a. Knowing the
relatively sluggish reactivity for the substitution on these pre-
cursors, we were pleased to obtain some of the unprecedented
hydroamination product (Scheme 5). Efforts to improve the
In conclusion, we have optimized the substitution reaction of
O-isocyanates to form N-oxyureas using bench-stable oxy-
carbamates as masked O-isocyanates. These conditions allowed
for high yields for alkyloxy or acyloxy-substituted products and
somewhat lower yields for the N-hydroxyureas. Nucleophilic
primary and secondary amines are well-tolerated under the opti-
mized conditions. Notably, many oxygen-substituents were well-
tolerated and N−O bond cleavage was only observed for the most
electron-withdrawing substituents. A cascade reaction involving
the substitution of an O-isocyanate and subsequent Cope-type
hydroamination was established: cyclic N-hydroxyureas could be
obtained from allyl amines. Overall, this work provides an improved
method to form N-oxyureas and demonstrates the controlled
reactivity possible when using masked O-isocyanates. Given the
amphoteric nature of the under-utilized O-isocyanate intermediate
and the broad uses of hydroxylamines, we anticipate further
applications exploiting this versatile building block.
Scheme 5. Cascade O-Isocyanate Substitution and Cope-Type
Hydroamination of Hydroxy-Carbamates
a
a
ASSOCIATED CONTENT
Supporting Information
Conditions: carbamate (1.0 equiv), allylamine (1.0 equiv), TfNH2
■
(
2
0.5 equiv) in EtOAc (0.2 M), heat in μW to 175 °C for 20 min to
*
S
.5 h. Isolated yields are shown.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03288.
overall yield of the cyclic products (5a−g) by isolating the
hydroxyurea intermediates and submitting them to the hydro-
amination reaction conditions did not improve this reac-
tivity [see Supporting Information (SI) for details]. Given the
importance of additives and of hydrogen-bonding for difficult
Additional optimization data (Tables S1−S3), complete
experimental procedures, characterization data, studies
securing the structural assignment of products in Scheme 5,
and NMR spectra (PDF)
19
Cope-type hydroaminations, we screened several additives in
hopes that the cascade could be improved. Gratifyingly, TfNH2
proved effective for most substrates. The cascade reaction
with symmetrical and bulky secondary allylamines pro-
ceeded with reliable, albeit somewhat modest yields (5a, 5b).
Using allylamine homologues furnishes the six-membered ring in
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: andre.beauchemin@uottawa.ca.
ORCID
2
0
lower yields, in agreement with established reactivity trends in
́
Andre M. Beauchemin: 0000-0003-0667-6215
C
DOI: 10.1021/acs.orglett.7b03288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Author Contributions
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†These authors contributed equally.
(
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Notes
(
The authors declare no competing financial interest.
D. A.; Wicks, Z. W. Prog. Org. Coat. 1999, 36, 148. (b) Wicks, D. A.;
Wicks, Z. W. Prog. Org. Coat. 2001, 41, 1. (c) Delebecq, E.; Pascault, J.-
P.; Boutevin, B.; Ganachaud, F. Chem. Rev. 2013, 113, 80.
(12) (a) Ivanovich, R. A.; Polat, D. E.; Beauchemin, A. M. Adv. Synth.
Catal. 2017, DOI: 10.1002/adsc.201701046. (b) Wang, Q.; An, J.;
Alper, H.; Xiao, W.-J.; Beauchemin, A. M. Chem. Commun. DOI:
ACKNOWLEDGMENTS
■
We thank the University of Ottawa and NSERC for generous
financial support. M.A.A. and R.A.I. thank NSERC for graduate
scholarships.
1
0.1039/c7cc07926e.
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(
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(
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(
(
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́
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(
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(
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(
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(
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̌
̌
́
̌
́
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(
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DOI: 10.1021/acs.orglett.7b03288
Org. Lett. XXXX, XXX, XXX−XXX